Oral drug delivery system

ABSTRACT

Dosage forms and drug delivery devices suitable for administration of pharmaceutical compounds and compositions, including the oral drug administration of compounds.

This application claims the benefit of U.S. Provisional Application No.60/433,116, filed Dec. 13, 2002, and of U.S. Provisional Application No.60/517,464, filed Nov. 4, 2003.

This application is a continuation of co-pending U.S. application Ser.No. 10/737,144, filed on Dec. 15, 2003, herein incorporated byreference.

FIELD OF THE INVENTION

The invention relates to dosage forms comprising formulations of drugs.More specifically, this invention relates to formulations that includeHigh Viscosity Liquid Carrier Materials (HVLCMs) and their use todeliver drugs.

BACKGROUND

Techniques and compositions for drug delivery of pharmaceuticals,including oral delivery, are well known. For example antihistamines,decongestants and antacids are all commonly delivered in solid tabletform. Analgesics have been delivered orally in tablet form for manyyears, for example salicylic acid, morphine, Demerol™ (meperidine),codeine and Percocet™ (oxycodone). Controlled release and sustainedrelease pharmaceutical compositions have also been available for manyyears; for example the Contac 400 Time Capsule™ (PhenylpropanolamineHydrochloride and Chlorpheniramine Maleate), anti-psychotics, melatoninformulations provide release of an active agent over several hours.Analgesics are of particular interest for controlled releaseformulations, and common controlled release formulations for analgesicsinclude the OxyContin® (oxycodone), MS Contin™ (morphine), CS Contin™(codeine).

Formulation of drugs for delivery, particularly oral delivery, posescertain challenges. One challenge is to produce an oralcontrolled-release dosage form that provides for a relatively steadydose of drug over the approximately eight hours during which the dosageform passes through the gastrointestinal tract. Sustained release isoften achieved by providing the tablet with a coating that delaysrelease, or by formulating the tablet in such a way that itdisintegrates relatively slowly, releasing drug as it does so. A tablet,however, once ingested, is subject to considerable mechanical andchemical stresses as it passes through the esophagus, stomach, duodenum,jejunum, ileum, large intestine and colon, thus providing a significantchallenge in maintaining controlled release of the drug formulation.Acids, enzymes and peristalsis can cause the tablet to break apart,resulting in exposure of the inside of the tablet and an increase insurface area of the tablet material. This will tend to increase thedelivery rate of the drug or otherwise adversely affect the controlledrelease properties of the dosage form.

Another challenge, is to produce a dosage form, including an oral dosageform, that reduces the potential for drug abuse. In particular, opioids,CNS-depressants, and stimulants are commonly abused. According to a 1999study by the National Institute on Drug Abuse (NIDA), an estimated 4million people, about 2 percent of the population age 12 and older, were(at the time of the study) using prescription drugs “non-medically.” Ofthese, 2.6 million misused pain relievers, 1.3 million misused sedativesand tranquilizers, and 0.9 million misused stimulants.

While many prescription drugs can be abused, the most common classes ofabused drugs are: (1) Opioids—often prescribed to treat pain, (2) CNSDepressants—used to treat anxiety and sleep disorders, and (3)Stimulants—prescribed to treat narcolepsy and attentiondeficit/hyperactivity disorder.

Opioids are a class of potent narcotics that includes, for example,morphine, codeine, oxycodone and fentanyl and related drugs. Morphine isoften used to alleviate severe pain. Codeine is used for milder pain.Other examples of opioids that can be prescribed to alleviate paininclude oxycodone (e.g. OxyContin®—an oral, controlled release form ofthe drug); propoxyphene (e.g. Darvon™); hydrocodone (e.g. Vicodin™);hydromorphone (e.g. Dilaudid™); and meperidine (e.g. Demerol™).

In addition to relieving pain, opioids can also produce a sensation ofeuphoria, and when taken in large doses, can cause severe respiratorydepression which can be fatal.

CNS depressants slow down normal brain function by increasing GABAactivity, thereby producing a drowsy or calming effect. In higher doses,some CNS depressants can become general anesthetics, and in very highdoses may cause respiratory failure and death. CNS depressants arefrequently abused, and often the abuse of CNS depressants occurs inconjunction with the abuse of another substance or drug, such as alcoholor cocaine. Many deaths occur yearly through such drug abuse. CNSdepressants can be divided into two groups, based on their chemistry andpharmacology: (1) Barbiturates, such as mephobarbital (e.g. Mebaral™)and pentobarbital sodium (e.g. Nembutal™), which are used to treatanxiety, tension, and sleep disorders. (2) Benzodiazepines, such asdiazepam (e.g. Valium™), chlordiazepoxide HCl (e.g. Librium™), andalprazolam (e.g. Xanax™), which can be prescribed to treat anxiety,acute stress reactions, and panic attacks. Benzodiazepines that have amore sedating effect, such as triazolam (e.g. Halcion™) and estazolam(e.g. ProSom™) can be prescribed for short-term treatment of sleepdisorders.

Stimulants are a class of drugs that enhance brain activity—they causean increase in alertness, attention, and energy that is accompanied byincreases in blood pressure, heart rate, and respiration. Stimulants arefrequently prescribed for treating narcolepsy, attention-deficithyperactivity disorder (ADHD), and depression. Stimulants may also beused for short-term treatment of obesity, and for patients with asthma.

Stimulants such as dextroamphetamine (Dexedrine™) and methylphenidate(Ritalin™) have chemical structures that are similar to key brainneurotransmitters called monoamines, which include norepinephrine anddopamine. Stimulants increase the levels of these chemicals in the brainand body. This, in turn, increases blood pressure and heart rate,constricts blood vessels, increases blood glucose, and opens up thepathways of the respiratory system. In addition, the increase indopamine is associated with a sense of euphoria that can accompany theuse of these drugs.

Taking high doses of a stimulant can result in an irregular heartbeat,dangerously high body temperatures, and/or the potential forcardiovascular failure or lethal seizures.

Taking high doses of some stimulants repeatedly over a short period oftime can lead to hostility or feelings of paranoia in some individuals.

A common and particularly dangerous cocktail of drugs is produced whenstimulants are mixed with antidepressants or over-the-counter coldmedicines containing decongestants. Anti-depressants may enhance theeffects of a stimulant, and stimulants in combination with decongestantsmay cause blood pressure to become dangerously high or lead to irregularheart rhythms, which in extreme cases may be fatal.

Solid dosage forms are particularly susceptible to abuse. For example,tablets oral drug delivery can be ground down into a powder. Drugaddicts and abusers grind down the tablet in order to nasally inhale thedrug. Addicts also grind the tablet to extract the drug into alcohol orwater to make a concentrated injectable drug solution. Administration ofvarious abused drugs in this way produces a sudden high dose of druginto the blood stream making the user euphoric. These well-knowntechniques for drug abuse have been used for many years with all mannerof drugs.

One particularly important example of a highly addictive drug that iscommonly abused by crushing (for nasal inhalation), and/or alcohol orwater extraction (for intravenous injection) is Oxycodone. Oxycodone isa powerful analgesic that is available in tablet form (Oxycontin®,Purdue Pharmaceuticals) and is manufactured in 10 mg, 20 mg, 40 mg, 80mg, and 160 mg tablet strengths. The Oxycontin® tablets are formulatedas time-release tablets (about 12 hours of release), but of coursecrushing and grinding down the tablet destroys any controlled-releaseproperties. It has been alleged that Oxycontin® abuse has so farresulted in at least 120 deaths nationwide(http://www.stopoxycontinaddiction.com/oxycontin-addiction.htm). 5 mg ofOxycontin® has as much active ingredient (oxycodone) as one Percocet™.So chewing/snorting a crushed 40 mg Oxycontin® is like taking eightPercocet™ at once or a 80 mg Oxycontin® is like taking 16 Percocet™ allat once. Overdose produces small pupils, slow breathing, dizziness,weakness, seizures, the loss of consciousness, coma, and sometimesdeath.

The above problems present a clear and long-felt challenge to drugmanufacturers to produce drug dosage forms that also allow for desirabledrug release kinetics and reduced potential for abuse.

SUMMARY OF THE INVENTION

The invention relates to a dosage form comprising a formulation, theformulation comprising a drug, a HVLCM, a network former, and anoptional rheology modifier. The formulation may also include a solvent.In another aspect, the invention relates to an oral dosage formcomprising a formulation having a drug, wherein the formulation, uponexposure to an aqueous environment, forms a network within theformulation and an outer surface. The formulations of the invention showdesirable drug-release kinetics and/or abuse deterrence characteristics.

The invention relates to a drug delivery device comprising aformulation, the formulation comprising a HVLCM, a network former and anoptional rheology modifier, and, in certain embodiments also comprisinga solvent. In another aspect, the invention relates to a drug deliverydevice comprising a formulation, wherein the formulation, upon exposureto an aqueous environment, forms a network within the formulation and anouter surface. These devices can be used to deliver any type ofbiologically active compound including drugs for example opioids, CNSdepressants and stimulants. In a another embodiment, the inventionrelates to an oral dosage form comprising a formulation, the formulationcomprising a HVLCM and an opioid. In a more specific embodiment, theformulation contains oxycodone, sucrose acetate isobutyrate (SAIB),cellulose acetate butyrate (CAB), isopropyl myristate (IPM) and ethyllactate (EL).

A particular advantage of the dosage form and delivery device of theinvention is that, in a particular embodiment, it provides an oraldosage form comprising a formulation having a drug, comprising one ormore of an HVLCM, a network former, a rheology modifier, and a solvent,present in amounts effective to reduce the rate of extraction of thedrug, for example, with water, ethanol, or other solvents, whilesimultaneously providing desired drug release kinetics. This reducedrate of extraction contributes to abuse deterrence and reducing risk ofdiversion.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-4, and 11 are graphs that show representative results from anabuse-deterrence study. The units of the graphs are relative percentagecumulative release vs. time (minutes).

FIG. 5 is a graph from a representative dog pharmacokinetic (PK) studyshowing plasma concentration (ng/ml) vs. time (hr) for three SAIB softgelcaps containing oxycodone formulations (A, B and C); compared with anOxycontin® tablet.

FIG. 6 is a chemical schematic showing the structure of SAIB, which is ahydrophobic, fully esterified sucrose derivative, at a nominal ratio ofsix isobutyrates to two acetates.

FIG. 7 is a graph showing representative dissolution results of drug ina simulated gastrointestinal environment (cumulative % release vs.time).

FIG. 8 is a representative photograph of a 100% SAIB formulationfollowing exposure to temperature at −80° C. (−112° F.) for eight hoursand crushing with a hammer. Note the controlled release matrix structureis preserved.

FIG. 9 is a representative photograph of a formulation comprisingSAIB+solvent, following exposure to temperature at −80° C. for eighthours and crushing with a hammer.

FIG. 10 is a representative photograph of a formulation of the invention(PTI-821, which is SAIB:EL:IPM:CAB at a ratio of 67:26:3:4) contained ina soft gelatin capsule, and containing 9 mg of drug) formulationfollowing exposure to temperature at −80° C. for eight hours andcrushing with a hammer.

SPECIFIC EMBODIMENTS OF THE INVENTION

Abbreviations used throughout the disclosure are as follows:

HVLCM: High Viscosity Liquid Carrier Material

SAIB: Sucrose Acetate Isobutyrate

EL: Ethyl Lactate

IM (or IPM): Isopropyl Myristate

CAB: Cellulose Acetate Butyrate

OC (or OXY): Oxycodone free base or salt

A derivative of a compound refers to any molecule the structure of whichis based on the structure of the original compound. The derivative mayhave substituted substituent groups or may have additional groups added,or may have groups removed, but it substantially shares the same corestructure as the original compound. Derivatives of compounds include forexample the free bases, salt, and the hydrates of such compounds.

Drug delivery device refers to a device for holding or containing andreleasing a drug wherein after administration of the drug deliverydevice to a subject, in particular, a human subject, the drug isreleased from the drug delivery device into a subject. The device forholding or containment may be any type of containment device, includinginjectable devices (pumps etc) and ingestible devices, including atablet, pill, capsule or formulation. Many drug delivery devices aredescribed in Encyclopedia of Controlled Drug Delivery (1999), EdithMathiowitz (Ed.), John Wiley & Sons, Inc.

Drug refers to any substance intended for use in the diagnosis, cure,mitigation, treatment, or prevention of any disease, disorder, orcondition or intended to affect the structure or function of the body,other than food. It can include any beneficial agent or substance thatis biologically active or meant to alter animal physiology Dosage formrefers to a drug and a drug delivery device.

Formulation refers to one or more ingredients or compounds. For example,a drug formulation is any drug combined together with anypharmaceutically acceptable excipients, additives, solvents, carriersand other materials.

High Viscosity Liquid Carrier Materials (HVLCMs) refers tonon-polymeric, non-water soluble liquids with a viscosity of at least5,000 cP at 37° C. that do not crystallize neat under ambient orphysiological conditions. HVLCMs may be carbohydrate-based, and mayinclude one or more cyclic carbohydrates chemically combined with one ormore carboxylic acids, such as Sucrose Acetate Isobutyrate (SAIB).HVLCMs also include nonpolymeric esters or mixed esters of one or morecarboxylic acids, having a viscosity of at least 5,000 cP at 37° C.,that do not crystallize neat under ambient or physiological conditions,wherein when the ester contains an alcohol moiety (e.g., glycerol). Theester may, for example comprise from about 2 to about 20 hydroxy acidmoieties. Various HVLCMs used with the present drug-delivery system aredescribed in U.S. Pat. Nos. 5,747,058; 5,968,542; and 6,413,536, allincorporated by reference hereby. The present invention may employ anyHVLCM described in these patents but is not limited to any specificallydescribed compounds.

Rheology modifier refers to a substance that possesses both ahydrophobic and a hydrophilic moiety. Rheology modifiers used with theinvention generally have a logarithm of octanol-water partitioncoefficient of between about −7 and +15, preferably between −5 and +10,more preferable between −1 and +7. Rheology refers to the property ofdeformation and/or flow of a liquid, and rheology modifiers are used tomodify viscosity and flow of a liquid formulation. Rheology modifiersinclude, for example, caprylic/capric triglyceride (Migliol 810),isopropyl myristate (IM or IPM), ethyl oleate, triethyl citrate,dimethyl phthalate, and benzyl benzoate.

Network former refers to a compound that forms a network structure whenintroduced into a liquid medium (such as a HVLCM). Network formers maybe added to the liquid formulation (such as a HVLCM) such that, uponexposure to an aqueous environment, they form a three dimensionalnetwork within the formulation. Network formers include, e.g., celluloseacetate butyrate, carbohydrate polymers, organic acids of carbohydratepolymers and other polymers, hydrogels, as well as particles such assilicon dioxide, ion exchange resins, and/or fiberglass, that arecapable of associating, aligning or congealing to form three dimensionalnetworks in an aqueous environment.

Solvents refers to any substances that dissolve another substance(solute). Solvents may be used in an HVCLM formulation to dissolve othercomponents such as drugs, network formers, rheology modifiers andstabilizers. Solvents may include alcohols, organic acids and theirderivatives, esters of organic acids, and compounds possessing analcohol and an organic acid residue e.g., ethyl lactate (EL) ortriacacetine, dimethyl sulfoxide (DMSO), propylene carbonate,N-methylpyrrolidone (NMP), ethyl alcohol, benzyl alcohol, glycofurol.

Stabilizer refers to any substance used to inhibit or reduce degradation(e.g., chemical) of other substances with which the stabilizer is mixed.Exemplary stabilizers typically are antioxidants that prevent oxidativedamage and degradation, e.g., sodium citrate, ascoryl plamitate, vitaminA, and propyl gallate and/or reducing agents.

In situ refers to laboratory conditions simulating conditions in the GItract of a mammal (see table 1).

Placebo refers to formulations without active drug (e.g., “a placebosolution” in Table 1).

DETAILED DESCRIPTION

Please note that the examples described herein are illustrative only andin no way limit the scope of the invention.

Dosage forms and drug-delivery devices suitable for delivery of a drugare disclosed. Certain of these devices are suitable for the oraldelivery of a drug. The dosage form or device includes a formulationthat includes an HVLCM and one or more of a network former, an optionalrheology modifier and/or a solvent. In particular, the formulation canbe loaded with a drug, and will release the drug over a period of timewhen in an aqueous environment, and in particular, an environmentsimilar to that of the GI tract of a mammal. While not wishing to bebound by theory, it is believed that the network former allows theformation of a micro-network within the formulation upon exposure to anaqueous environment. This micro-network formation appears to be due, atleast in part, to a phase inversion (e.g., a change in glass transitiontemperature, T_(g)) of the network former. The result is believed to bea skin or surface layer of precipitated network former at the interfacebetween the dosage form and the aqueous environment of the GI tract, aswell as the formation of a three-dimensional micro-network ofprecipitated network former within the dosage form.

Preferred dosage forms comprising drug delivery devices of the inventiondo not become substantially emulsified during passage through the GItract, but substantially maintain their integrity (deformability and/orsurface characteristics), while passing through the GI tract andreleasing drug. While not wishing to be bound by any theory, it isbelieved that the formulation forms a network on the surfaces and/or inthe bulk phase. The surfaces are renewed, such that the concentrationgradient is maintained at the surfaces for desirable drug releasekinetics. This phenomenon was observed by the inventors during the dogplasma PK study that produced the results as shown in FIG. 5. The dosageform when exiting the GI tract may retain a substantial proportion ofits weight; for example, desirable dosage forms can have a weight thatis no less than about 50% of the weight of the dosage form upon oraladministration. This percentage weight may vary with differentformulations used in dosage forms, and may be at least 60%, 70%, 80%, oreven 90% of the original weight.

In preferred embodiments, the formulation comprises a HVLCM along withvarious additives and excipients. HVLCMs used in certain embodiments aregenerally hydrophobic, non-polymeric, non-water soluble liquids with aviscosity of at least 5,000 cP at 37° C. that do not crystallize neatunder ambient or physiological conditions. Various HVLCMs used with theinvention are described in U.S. Pat. Nos. 5,747,058; 5,968,542; and6,413,536 and in U.S. Ser. Nos. 09/699,002, filed Oct. 26, 2000 and10/316,441, filed Dec. 10, 2002, the entire contents of which areincorporated herein by reference. Sucrose Acetate Isobutyrate (SAIB) hasbeen found to be a particularly suitable HVLCM for many of theapplications described herein.

The dosage forms and drug delivery devices of the invention can be usedto deliver any type of biologically active compound. Examples of suchbiologically active compounds delivered using the invention includeopioids, CNS depressants and stimulants, as well as proteins, hormones,chemotherapeutic agents, anti-nausea medication, antibiotics, antiviralsand other agents. One class of drug of particular interest for deliveryusing the system disclosed herein is opioids, which includes alfentanil,allylprodine, alphaprodine, anileridine, apomorphine, apocodeine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone,methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papavereturn,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,pholcodine, piminodine, piritramide, propheptazine, promedol, profadol,properidine, propiram, propoxyphene, remifentanyl, sufentanyl, tramadol,tilidine, naltrexone, naloxone, nalmefene, methylnaltrexone, naloxonemethiodide, nalorphine, naloxonazine, nalide, nalmexone, nalbuphine,nalorphine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate,(NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI),beta-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LY117413,MR2266, etorphine, DAMGO, CTOP, diprenorphine, naloxonebenzoylhydrazone, bremazocine, ethylketocyclazocine, U50,488, U69,593,spiradoline, DPDPE, [D-Ala2,Glu4] deltorphin, DSLET, Met-enkephalin,Leu-enkephalin, β-endorphin, dynorphin A, dynorphin B, a-neoendorphin,or an opioid having the same pentacyclic nucleus as nalmefene,naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine,dezocine, or their pharmacologically effective esters or salts.

The dosage form disclosed allows for the release of drug including overa prolonged period, such as of several hours. The total period forrelease of drug in an amount sufficient to be an effective dosage may begreater than 20 hours, or greater than 17 hours, or greater than 15hours, or greater than 12 hours, or greater than 10 hours, or greaterthan 8 hours, or greater than 6 hours, or greater than 4 hours, orgreater than 2 hours, or greater than 1 hour. The amount of drugsufficient to provide an effective dosage is determined from thetherapeutic range of the drug, which is determined from, for example,clinical trials, and this information is easily available to one ofskill in the art.

The drug delivery device disclosed may include various components inaddition to the carrier material (generally a HVLCM). The additionalcompounds may be present in amounts ranging from about 75 wt % to as lowas about 0.01 wt % of the total formulation. These additional componentsmay include the following types of compounds:

-   -   Solvents, e.g., ethyl lactate (EL) or triacetine, DMSO,        Propylene carbonate, NMP, Ethyl alcohol, Benzyl alcohol,        Glycofurol, alpha-tocoperol, Miglyol 810, isopropyl alcohol,        diethyl phthalate, PEG 400, triethyl citrate, benzyl benzoate.    -   Network formers, e.g., cellulose acetate butyrate (CAB 171-15,        CAB 381-2 and CAB 381-20, supplied by Eastman Chemicals, the        characteristics of which are described in Table 2); carbohydrate        polymers, organic acids of carbohydrate polymers and other        polymers, hydrogels, as well as particles such as silicon        dioxide, ion exchange resins, and/or fiberglass, that are        capable of associating, aligning or congealing to form three        dimensional networks in an aqueous environment. Other examples        include cellulose acetate phthalate, ethyl cellulose, Pluronic,        Eudragit, Carbomer, hydroxyl propyl methyl cellulose, cellulose        acetates such as CA 381-2 and cellulose triacetate, PMMA, CAB        500-5.    -   Rheology modifiers, e.g., caprylic/capric triglyceride (Migliol        810), isopropyl myristate (IM or IPM), ethyl oleate, triethyl        citrate, dimethyl phthalate, and benzyl benzoate.    -   Stabilizers, e.g., antioxidants such as sodium citrate ascorbyl        palmitate, and propyl gallate and/or reducing agents. Other        examples include ascorbic acid, vitamin E, sodium bisulfite,        butylhydroxyl toluene, BHA, acetylcysteine, monothioglycerol,        phenyl-alpha-nathylamine, lecithin, EDTA.

These and other additional compounds (discussed in greater detail below)may be altered so as to control the rate of release of a drug and/or themaximum dosing (e.g. solubility) of a drug used with the drug deliverydevice of the invention (Handbook of Pharmaceutical Excipients 3^(rd)ed., A. Kibbe, Am. Pharm. Assn., pub.).

In certain embodiments, the orally-administered, drug delivery devicedisclosed may be formulated so as to produce particular controlledplasma levels of drug over a particular period. This is obviously ofgreat importance in maintaining a drug-plasma level within anappropriate therapeutic range. An appropriate therapeutic range willvary depending on the drug, but can range from femtogram/ml levels up toabove microgram/ml levels for a desired period of time. For example, asingle dose of a drug dosage form disclosed herein may result inmaintenance of plasma levels of a drug at greater than 5 ng/ml for aperiod of greater than 8 hours (See FIG. 5, discussed in detail below).In other embodiments, the drug plasma level achieved using a single dosemay be greater than 5 ng/ml for a period of greater than 10 hours,greater than 12 hours, greater than 14 hours, greater than 16 hours,greater than 18 hours, or greater than 20 hours. In yet otherembodiments, the drug plasma level achieved using a single dose may begreater than 5 ng/ml, greater than 10 ng/ml, greater than 15 ng/ml,greater than 20 ng/ml, greater than 30 ng/ml, greater than 40 ng/ml,greater than 50 ng/ml for a period of 4, 8, 10, 12, 14, 16, 18 or 20hours.

The maximum plasma concentration of drug may be reached at a timefollowing administration from between 0.1 hr to about 24 hr, or fromabout 0.25 hr to 10 hr, or from about 0.25 hr to 8 hr, or from about 0.5hr to 6 hr, or from about 0.5 hr to 4 hr, or from about 0.5 hr to 2 hr,or from about 0.5 hr to 1 hr. The time to maximum plasma concentrationmay be adjusted by adjusting various components of the drug deliverydevice as taught herein. Altering components alters viscosity or otherrheological characteristics of the formulation and concomitantly altersrate of drug release (discussed in detail below). The rate of reductionof plasma drug concentration over time may also be adjusted by varyingcomponents of the drug delivery device. Any desired release profile maybe achieved by altering components as described herein.

The plasma levels obtained may be adjusted by adjusting the formulationand other components of the drug delivery device, and desirable plasmalevels will depend on the therapeutic range or its index for anyparticular drug. It is readily within the skill of one in the art todetermine the desired therapeutic index, and in view of the currentdisclosure, it would be a matter of routine experimentation to adjustthe various components in order to achieve the desired releasecharacteristics for a particular drug.

In certain embodiments, the release profile of drug over the releaseperiod is preferably approximately steady over time, sufficient toprovide a therapeutic dose over the release period, and preferably showsa decreased burst effect when compared to a standard tablet formulation.As can be seen from FIG. 7 (discussed in more detail later), the drugdelivery device of the invention can release drug (in this case,oxycodone) at an approximately steady rate over a period of at least 24hours. The release rate is particularly steady from about 1 hr togreater than 24 hrs. This is in contrast to a commercial tabletformulation (OxyContin®) that provides substantial drug release duringthe first 5 hr period. In the case as shown in FIG. 7, the dosage formusing the drug delivery device of the invention provides a long term invitro release with less than 40% of drug released within 24 hours,whereas the commercial dosage form provides nearly 100% release in 24hours. The time to 90% release of drug may be varied by varying theformulation and other device components and may be as little as 4 hours,6 hours, 8 hours, 10, hours, 12 hours, 16 hours or 20 hours, or up toabout 24 hours.

The rate of drug release from the dosage form may be varied depending onthe drug used and dosage required. Release rates may be different indifferent parts of the GI tract, and release rates may be averaged overthe time of transit through the GI tract (approximately 8-24 hrs).Typical average release rates may vary substantially. For many drugs,they may range from about 0.01 to 500 mg/hr, from 0.5 to 250 mg/hr, 0.75to 100 mg/hr, 1.0 to 100 mg/hr, 2.0 to 100 mg/hr, 5 to 100 mg/hr, 10 to100 mg/hr, 10 to 80 mg/hr, 20 to 50 mg/hr, or about 20 to 40 mg/hr.

Dosage regimens for the drug may be determined by the physician inaccordance with standard practices. Once per day or twice per day (BID)dosing may be used to maintain a sufficient clinical effect, e.g., tomaintain pain relief.

An important advantage of the dosage forms disclosed herein is that theyhave abuse-deterrent characteristics and/or reduced risk of diversion.The dosage form, and the formulation contained therein is notsusceptible to crushing, powdering or extraction using ethanol or water.Specifically, HVLCM is a viscous liquid, and so formulations containingHVLCMs avoid the possibility of crushing for the purpose of inhalation.Additionally, the formulation of the invention has the characteristic ofbeing resistant to drug extraction using ethanol or water, when comparedto a tablet formulation of a drug.

In certain preferred embodiments, the drug-delivery device is composedof a drug formulation encapsulated within an enclosure or capsule,preferably biodegradable, such as a capsule or a gelatin capsule(“gelcap”), wherein the capsule is made of a substance that degrades orotherwise dissociates when exposed to conditions present in thegastro-intestinal tract of a mammal. Capsules and gelcaps are well knownin drug delivery technology and one of skill could select such a capsuleas appropriate for delivery of a particular drug. Once the capsule hasdissolved or dissociated from the formulation, the formulation of theinvention generally remains intact, especially for hydrophobicformulations, and passes through the GI tract without emulsification orfragmentation.

In certain more specific embodiments the invention encompasses an oraldosage form comprising a formulation contained within a biodegradablecapsule, wherein the formulation comprises a drug and a HVLCM, andwherein the capsule is made of a substance that degrades when exposed toconditions present in the gastro-intestinal tract of a mammal. Incertain embodiments the capsule comprises gelatin or synthetic polymerssuch as hydroxyl ethyl cellulose and hydroxyl propylmethyl cellulose.Gelcaps can be of the hard or soft variety. Gelatin capsules are wellsuited for delivering liquid formulations such as vitamin E andcod-liver oil. Gelatin capsules are stable in storage, but once in theacid environment of the stomach (low pH less than about pH 4-5), thegelcap dissolves over a 10-15 minute period. In certain embodiments, thedrug delivery device further comprises at least one component selectedfrom the group consisting of: Ethyl Lactate, Triacetin, PropyleneCarbonate, Glycofurol, Triethyl Oleate, Isopropyl Myristate, CelluloseAcetate Butyrate, and derivatives thereof.

Certain preferred embodiments of the orally-administered, drug-deliverydevice of the invention comprise Sucrose Acetate Isobutyrate (SAIB) asthe HVLCM carrier material. SAIB is a non-polymeric highly viscousliquid at temperatures ranging from −80° C. to over 10° C., it is afully esterified sucrose derivative, at a nominal ratio of sixisobutyrates to two acetates (FIG. 6). It is manufactured by EastmanChemical Company as a mixed ester, and the resulting mixture does notcrystallize but exists as a very viscous liquid. It is a hydrophobic,non-crystalline, low molecular weight molecule that is water insolubleand has a viscosity that varies with temperature. For example, pure SAIBexhibits the viscosity of approximately 2 million centipoise (cP) atroom temperature and approximately 600 cP at 80 C. SAIB has uniquesolution-viscosity relationship in that the SAIB solutions in a numberof organic solvents is significantly lower than these viscosity valuesfor the pure SAIB and therefore the SAIB-organic solvent solutionsrender themselves capable of processing using conventional equipmentsuch as mixers, liquid pumps and gelcap production machines. SAIB alsohas applications in drug formulation and delivery, for example asdescribed in U.S. Pat. Nos. 5,747,058, 5,968,542, 6,413,536, 6,498,153,all incorporated by reference herein. In the present invention, SAIB maybe used as the HVLCM and may be present in quantities that varysignificantly. For example, quantities of at least about 50, 60, 70, 80,90, 95, 97, 98, 99, 99.5 or 99.9 wt % can be used. Various formulationscontaining SAIB are discussed in the examples.

In addition, certain embodiments of the drug delivery device asdisclosed allow the oral delivery of compounds, such as proteins, thatwould not normally be considered effectively orally administrablebecause administration in conventional oral compositions would likelyresult in the breakdown of the active agent by stomach acids or enzymes.

One embodiment of the invention relates to opioid dosage forms suitablefor oral administration, including those that provide desirable drugrelease kinetics and/or limit the likelihood that diversion of theopioids in the dosage forms could occur by patients or others. In thisembodiment, the opioids can be dissolved or dispersed in the formulationcomponent of the invention, which can be simply a HVLCM. Suitable opioidcompounds deliverable according to the invention include, for example,those generally used as pain relievers, narcotics and/or anesthetics,and include alfentanil, allylprodine, alphaprodine, anileridine,apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, cyclorphen,cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,normorphine, norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone,papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, pholcodine, piminodine, piritramide, propheptazine,promedol, profadol, properidine, propiram, propoxyphene, remifentanyl,sufentanyl, tramadol, tilidine, naltrexone, naloxone, nalmefene,methylnaltrexone, naloxone methiodide, nalorphine, naloxonazine, nalide,nalmexone, nalbuphine, nalorphine dinicotinate, naltrindole (NTI),naltrindole isothiocyanate, (NTII), naltriben (NTB), nor-binaltorphimine(nor-BNI), beta-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864,LY117413, MR2266, etorphine, DAMGO, CTOP, diprenorphine, naloxonebenzoylhydrazone, bremazocine, ethylketocyclazocine, U50,488, U69,593,spiradoline, DPDPE, [D-Ala2,Glu4] deltorphin, DSLET, Met-enkephalin,Leu-enkephalin, β-endorphin, dynorphin A, dynorphin B, a-neoendorphin,or an opioid having the same pentacyclic nucleus as nalmefene,naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine,dezocine, or their pharmacologically effective esters or salts.

The oral dosage forms of these opioids may be prepared by simply mixinga HVLCM, a rheology modifier, a network former, the active agent, asolvent and any additives, and introducing the resulting mixture into agelatin capsule. Alternative formulations may include emulsifying themixture in water, and introducing this emulsion into the gelatincapsule, or using one or more of the techniques described herein toproduce the dosage form.

In another embodiment of the invention, the HVLCM can be used as thecontinuous phase in a dispersion of particulate biologically activeagent. For example, SAIB, which is extremely viscous, can be used tosuspend particles of lyophilized protein, microparticles, microspheres,or microcapsules of drugs, for example, biologically active agents, toproduce suspension formulations. Concentrations of the active agent inthe suspension formulation are analogous to those disclosed above. Theresulting suspension formulation has excellent storage stability.

Preferred embodiments of this invention provide an effective,user-friendly and inexpensive ingestible oral dosage form that allowssustained drug release, with favourable drug-release kinetics, duringtransit through the gastro-intestinal tract, and is less subject toabuse than current tablet and capsule dosage forms. The inventionencompasses a controlled release oral drug delivery device. One drugdelivery device of this invention encompasses a SAIB-drug formulationwhich may be enclosed in a gelatin capsule suitable for oral delivery.Different embodiments may use some or all of the following additionalcomponents in the formulation to effect appropriate drug deliverykinetics: Solvents, e.g., ethyl lactate (EL) or triacacetine, DMSO,Propylene carbonate, NMP, Ethyl alcohol, Benzyl alcohol, Glycofurol.Network formers, e.g., cellulose acetate butyrate (CAB 171-15, CAB 381-2and CAB 381-20 supplied by Eastman Chemicals). Rheology modifiers, e.g.,caprylic/capric triglyceride (Migliol 810) and other plasticizers suchas isopropyl myristate (IM or IPM), triethyl citrate, dimethylphthalate, and ethyl oleate, benzyl benzoate. Stabilizers, e.g.,antioxidants such as sodium citrate ascoryl plamitate, and propylgallate. A specific example of a formulation for use in the drugdelivery device of the invention contains oxycodone free base and/orhydrochloride salt, SAIB, ethyl lactate, isopropyl myristate, and CAB.An exemplary embodiment, used by the inventors to produce data disclosedherein, is formulated as follows: oxycodone free base 10 mg per gelcap,SAIB 65%, ethyl lactate 27%, isopropyl myristate 3% and CAB 381-20 5%(all percentages are weight percent). This formulation is placed into asoft gelcap.

The dosage form of the invention may comprise one or more drugs. Theamount of drug(s) and percentages of components in the formulation mayvary. Typical average amounts may vary substantially. For many drugs,they may range from about 0.1 mg to 1000 mg, or from about 1 mg to 500mg, or from about 2 mg to 250 mg, or from about 2 mg to 250 mg, or fromabout 2 mg to 150 mg, or from about 5 mg to 100 mg, or from about 5 mgto 50 mg. The precise amount of drug desired can be determined byroutine methods well known to pharmacological arts, and will depend onthe type of drug, and the pharmacokinetics and pharmacodynamics of thatdrug.

The percent weight of HVLCMs may vary depending on the characteristicsof the dosage form desired, and may be for example include from about30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, to about 100%.Exemplary formulations disclosed herein contain 99%, 71%, 70%, 65%, 63%,61.6%, 59%, 50%, 40%, 30%, 20% or even lesser amounts of SAIB. Variationin SAIB content may be made to alter viscosity or other rheologicalproperties of the formulation and to alter the rate at which drug isdelivered. Using the information presented here, ones skilled in the artcould alter the SAIB content of the formulation to suit various drugs ofdiffering hydrophobicity or hydrophilicity, and determine the optimumrate of drug release from the formulation.

The dosage form of the invention may comprise one or more solvents. Thepercent weight of solvent(s) (such as EL) may vary depending on thecharacteristics of the dosage form desired, and may be for example fromabout 0% to about 60%, or from about 20% to about 50%, or from about 25%to about 48%. Exemplary formulations disclosed herein include those with48%, 45%, 36.3%, 31.4%, 29.5%, 29%, 27%, and 23% EL. Again, using theinformation presented herein, ones skilled in the art could adjust thepercent of solvent and determine the optimum amount required fordelivery of a particular drug. More than one solvent can be used in aSAIB formulation.

The dosage form of the invention may comprise one or more rheologymodifiers. The percent weight of rheology modifier(s) may vary dependingon the characteristics of the dosage form desired, and may be forexample vary from about 0.1% to about 10%, or from about 0.5% to about5%, or from about 1% to about 4%. Exemplary formulations disclosedherein include those with 3.5%, 3%, and 1%, and 0%, IM. Using theinformation presented herein, ones skilled in the art could adjust thepercent of formulation viscosity or other rheology modifier anddetermine the optimum amount required for delivery of a particular drug.More than one rheology modifier can be used in a SAIB formulation.

The percent weight of network former(s) may vary depending on thecharacteristics of the dosage form desired, and may be for example fromabout 0% to about 20%, or from about 0.1% to about 10%, or from about0.5% to about 9%, or from about 1% to about 8.6%. Exemplary formulationsdisclosed herein include those with 8.6%, 7.8%, 5%, 4.5%, 3%, 2.1%, 2%,1%, 0.5% and 0% CAB. Different types of CAB (e.g., CAB 381-20, CAB381-2, and CAB 171-15) may be used to affect desired drug releasecharacteristics. Again, using the information presented herein, onesskilled in the art could adjust the percent of the network former anddetermine the optimum amount required for delivery of a particular drug.More than one network former can be used in a SAIB formulation.

The formulations of the invention may use network formers such ascellulose acetate butyrate of varying acetyl and butyryl content such asCAB 381-20, CAB 381-2 and CAB 171-15. CAB allows the in-situ formationof a micro-network within the SAIB-drug formulation. Although notwishing to be bound by theory, it appears that the mechanism ofmicro-network formation appears in part to be due to phase inversion(e.g., change in T_(g)) of network formers. That is to say, when SAIBformulations containing the CAB type of network former (for example CAB381-20) are exposed to or immersed in aqueous environments such as themammalian gastrointestinal (GI) tract, previously dissolved networkformers in SAIB formulations will precipitate as a result of migrationof water and other biologically available fluid components, which willresult in polymer precipitation process and yield polymeric networkswithin the drug delivery device. The formation of micro-network willbegin at the surface of the formulation mass and the polymeric networkwill gradually propagate toward the center of the formulation mass,resulting in a progressive increase in SAIB formulation viscosity insitu.

In conjunction with the network formers, solvents such as ethyl lactate,and rheology modifiers such as isopropyl myristate, when formulated intoSAIB, appear to confer a number of unexpected characteristics to theHVLCM formulations. The characteristics include rheological (e.g.,viscosity) characteristics, drug release kinetics, and abuse-deterrencecharacteristics.

It was discovered that the drug release rates in the early and/or latetime periods increased with increasing content of the network formingpolymers in the presence of varying concentration of ethyl lactate andisopropyl myristate. However, the effects of ethyl lactate (EL) varied,and, for example, during early time periods (0-6 hours) increasing ELconcentration increased the drug release rate while in late time periods(from 6-24 hours), the drug release rate decreased with increasingconcentration of EL. Also, notably, drug extractability from SAIB drugformulations using ethanol solutions consistently decreased withaddition of CAB polymers regardless of the concentrations of ethyllactate and isopropyl myristate.

Also, it was discovered that addition of CAB polymer in SAIBformulations consistently raised the viscosity of the SAIB formulationsbefore and after immersion in 37° C. aqueous media. However, theaddition of other components i.e., ethyl lactate and isopropyl myristatewas discovered to decrease viscosity before water immersion, butincrease viscosity following the immersion in water. These observationsare highly unexpected based on a previous understanding of solvents andplasticizers in SAIB drug formulations.

The present invention allows for adjustment of a number of performancecharacteristics of HVLCM formulations by adjusting the ratios ofindividual formulation ingredients such as solvents, rheology modifiersand network formers, including optimization thereof. The currentinvention also discloses new and surprising interrelationships betweenthe formulation ingredients, which resulted in unique and non-obviousformulation rheology, drug release kinetics, rate and extent of drugabsorption in vivo, and/or desirable abuse deterrence characteristicsincluding reduced drug extractability, for example, by alcoholic oraqueous solutions.

The invention provides a dosage form that reduces or eliminates drugabuse wherein the route of abuse may include, for example snortable,inhalable, intravenous, sublingual, bucal, subcutaneous, percutaneous,vaginal, rectal or intraocular means. The present dosage form hasseveral important abuse-deterrent characteristics: it is non-crushable(for abusive nasal inhalation) and it provides a formulation, e.g., thatmakes alcohol-extraction or water-extraction of the drug very difficult,producing a poor drug yield.

The dosage forms of the invention show unexpectedly favourabledrug-release kinetics. For example, the SAIB/Oxycodone formulationprovides improved pharmacokinetic parameters such as shorter Tmax,greater and/or equivalent Cmax and AUC (area under curve) and improvedbioavailability of the drug when compared with a currently marketedformulation (e.g., OxyContin®).

Another unexpectedly favourable property of the formulation of theinvention is that the formulation bolus appears to stay substantiallyintact as it passes through the GI tract. For example, the SAIB-basedformulation is released from the gelatin capsule when the capsule isdissolved, but the formulation bolus itself is not emulsified as itpasses through the stomach, gut or colon despite being, it is believed,kneaded or deformed by GI motility (peristaltic motion). While notwishing to be bound by theory, it is believed that surface renewaloccurs by relatively constant renewal of surface drug concentration bydiffusion of the drug from the interior of the bolus, and by deformationand refolding of the surface, or by some combination of thesemechanisms.

In a particular embodiment, the invention provides an oral dosage formcomprising a formulation contained within a biodegradable capsule,wherein the formulation comprises a drug, a HVLCM, a rheology modifier,a network former and a solvent, and wherein the capsule is made of asubstance that degrades when exposed to conditions present in thegastro-intestinal tract of a mammal. In preferred embodiments, the HVLCMcan be SAIB, and the capsule can be made from gelatin or syntheticpolymers. In particular embodiments the drug may be an opioid such asoxycodone. The drug-release kinetics of dosage forms incorporatingvarious formulations can be seen to be both unexpected and favorable fordelivery of drugs such as oxycodone.

Preparation of Formulations

A method for preparation of an exemplary formulation of the invention,using SAIB as the HVLCM, is presented. Other SAIB formulations can beprepared by varying this method. The ratios refer to weight percentratios for SAIB/Ethyl lactate/Isopropyl Myristate/CAB 381-20,respectively.

A formulation comprising SAIB/EL/IPM/CAB (65:27:3:5) was made asfollows:

An appropriate amount ethyl lactate was placed in a beaker; whilestirring slowly CAB and IPM were added (stir bar on stir plate); allowedto go completely into solution (stir bar on stir plate)—resultingmixture was left at 37° C. for 3 days; hot (80° C.) SAIB (shake in hand,then place on stir plate) was added—65:27:3:5 mixture left over a periodof about 48 hrs at 37° C.; the mixture was heated to 70° C. for ˜2 hoursand homogenized with 20 mm probe at about 4000 rpm for 20-30 seconds;oxycodone-base was added (at 9 mg/g) and the mixture heated to 70° C.for 1 hr, then left overnight. The mixture was reheated to 70° C. tofill soft gelcaps using a hypodermic needle and matching syringe.

Formulations, Viscosity and Dissolution (Table 1)

Table 1 displays viscosity and dissolution data for variousformulations. Viscosity values were determined at 26° C. and 37° C.(+/−0.1 to 0.3° C.) using Brookfield Digital Rheometer Models LV DV IIIand HBDV and CPE 52 cone (n=1 ea). The content of oxycodone ranged from9 to 12 mg per gelcap in SAIB formulations (lot#X03502 contains onlySAIB and oxycodone).

In addition to the compositions of SAIB formulations, Table 1 also showsviscosity at 37° C. for the formulations, both before and afterimmersion in 37° C. water for 6 hours (the column marked “placebo−H₂0”refers to the viscosity of the solution before immersion in water, andthe column marked “placebo+H₂0” refers to the viscosity of the solutionfollowing immersion in water). The conditions of 37° C. and waterimmersion were intended to simulate in vivo conditions.

Table 1 also shows cumulative amount of oxycodone released (mg) duringtwo separate periods. One period is for 0 to 6 hours, and the other for6 to 24 hours.

Information in Table 1 was analyzed and the following semi-empiricalequations were derived (see equations 1-3). Equations 1-3 were derivedfrom the information in Table 1 for SAIB oxycodone gelcap formulationsX03511 to X03518 (8 different formulations).

Equation 1 demonstrates that the drug dissolution rate from timeintervals 0-6 hours increases with the increasing concentrations of EL,IPM and CAB polymers (statistical confidence is high, r=0.9).

Equation 2 shows that the drug dissolution rate from 6-24 hoursincreases with increasing IPM and CAB but decreases with increasing EL.

Equation 3 shows that the drug dissolution rate from 0 to 24 hoursincreases with the increasing EL, IPM and CAB.

The results embodied in the equations 1-3 are unexpected. One would haveexpected that increased CAB would decrease the dissolution rate. Insteadincreasing CAB appears to increase dissolution rate in the presence ofEL and IPM. In addition, the role of EL changes depending on the timeintervals of interest.

Equations 4-5 were calculated using formulation viscosity values beforeimmersion in 37° C. water for 6 hours. As can be seen in equations 4-5,the correlation coefficient is excellent (r2=0.93 to 0.96). Bothequations predict that viscosity will increase with increasing CAB whilethe viscosity will decrease with increasing EL and IPM. Based on thetheories of solution rheology, this was expected.

Equations 6-7 were derived from the formulation viscosity valuesfollowing immersion in water at 37° C. for 5 hours. As can be seen inthese equations, as expected, increasing CAB increases viscosityfollowing immersion in water. However, equation 6 and 7 both predictthat increasing EL increases the immersion viscosity. This isunexpected. One would expect that the effect of increasing EL onimmersion viscosity would be to decrease viscosity.

Table 1 displays data for the SAIB-oxycodone formulation X03502. X03502did not contain any formulation ingredients (pure SAIB), but it diddeliver a significant amount of oxycodone during the dissolution testing(0.42 mg over 0-6 hours and 0.65 mg over 6-24 hours). As can be seen bythe in situ viscosity data (51,200 cP), which is significantly reducedin situ, it released oxycodone at a low rate but with a good ratecontrol mechanism.

Table 1 also shows a number of other interesting formulations. Forexample X03503 (SAIB/IPM 99/1), which shows a significant rheologymodification effect of 1% IPM, showed higher drug delivery rate comparedwith pure SAIB formulation.

In addition, table 1 presents SAIB formulations containing CAB 171-15.As can be seen in formulations X03505 to X03508 viscosity before andafter immersion in water are quite significantly different from thoseformulations containing CAB 381-20BP. As a result SAIB oxycodoneformulations containing CAB 171-15 exhibited significantly differentrelease kinetics of oxycodone from those containing equivalent weightpercent of CAB 381-20.

Below are the semi-empirical equations that were deduced from thedissolution experiment data. The equations can be used to calculateOxycodone free base dissolution and extraction, and viscosity of placeboSAIB solutions before and after immersion in 37° C. Water for 5 hours.

1. Dissolution of Drug with Varying Wt % of Components

Cumulative drug dissolution was measured as functions of weight percentof EL, IPM and CAB 381-20BP. Eight SAIB-Oxycodone formulations withcorresponding in vitro dissolution data are shown. Formulations wereused in non GLP and GLP dog PK studies. Lots X03511 to X03518 (n=8).

For the following equations Y=cumulative amounts of drug dissolved (mg)or extracted (wt. %), and x1, x2 and x3 are the weight percents of EL,IPM and CAB 381-20BP, respectively.

a. Time Interval from 0 to 6 hrs.

$\begin{matrix}{\frac{1}{Y\; 1} = {{{3.02 - {0.15\sqrt{x\; 1}} - {0.5\sqrt{x\; 2}} - {0.37\sqrt{x\; 3}}}:r^{2}} = 0.9}} & \left( {{equation}\mspace{14mu} 1} \right)\end{matrix}$b. Time Interval from 6-24 hrs.

$\begin{matrix}{\frac{1}{Y\; 2} = {{{1.59 + {0.054\sqrt{x\; 1}} - {0.355\sqrt{x\; 2}} - {0.41\sqrt{x\; 3}}}:r^{2}} = 0.95}} & \left( {{equation}\mspace{14mu} 2} \right)\end{matrix}$c. Time Interval from 0-24 hrs.

$\begin{matrix}{\frac{1}{Y\; 3} = {{{1.05 - {0.002\sqrt{x\; 1}} - {0.21\left( {\sqrt{x\; 2} + \sqrt{x\; 3}} \right)}}:r^{2}} = {0.93.}}} & \left( {{equation}\mspace{14mu} 3} \right)\end{matrix}$2. Viscosity of Saib Placebo Solutions at 37° C. Before and afterImmersion in Water.(a) For SAIB Placebo Solutions Containing CAB 381-20BP (n=13) BeforeImmersion in Water at 37° C.:Z=3359.02−192.26x1−227.88x2+1240.29x3::r ²=0.93  (equation 4)

Alternative Correlation

Ln Z=8.47−0.1x1−0.137x2+0.585x3::r ²=0.96  (equation 5)(b) For SAIB Placebo Solutions Containing CAB 381-20BP (n=13) afterImmersion in Water @37° C. for 5 hours:Ln Z1=3.8+0.056x1−0.00911x2+1.02x3::r ²=0.96  (equation 6)Alternative Correlation isZ1=−42327.04+292.95x1+405.64x2+12173.84x3::r ²=0.8  (equation 7)

Where Z and Z1 are the viscosity (cP) of SAIB placebo solutions beforeand after immersion in 37° C. water for 5 hours.

The above equations and equation 8, given below, derived with respect toan exemplary drug (oxycodone) allow one to formulate dosage forms inwhich the abuse deterrence and drug release kinetics, as well as othercharacteristics, can be varied and optimized to any desired extent.Similar equations can be developed with respect to other exemplarydrugs.

TABLE 1 Rheological Characteristics and In Vitro Drug Release Attributesof SAIB Oxycodone Formulations Dissolution Attributes (mg of drugreleased Viscosity (cP) at 37° C. over 0-6 and 6-24 hr) CompositionPlacebo Placebo Σ 0-6 hr Σ 6-24 hr Lot # (wt %) −H20 +H20 (mg) (mg)X03502 SAIB 137,000 51,200 0.42 0.65 (100) X03503 SAIB/IPM 79,773 33,3380.63 0.78 (99/1) X03504 SAIB/EL/CAB 171-20 (50/48/2) X03505 SAIB/EL/CAB2,046 1.14 × 10E(6) 2.82 3.53 171-15 (50/45/5) X03506 SAIB/EL/CAB1,618-2,670 5,270-9,380 1.09/1.45 2.33/2.27 171-15 (70/27/3) X03507SAIB/EL/CAB 170-15 325 — (61.6/36.3/2.1) X03508 SAIB/EL/CAB 171-15 48262 1.21 2.76 (70/29.5/0.5) X03511 SAIB/EL/IMP/CAB 6,296 120e3 1.7 3.1381-20 BP (59/31.4/1/8.6) X03512 SAIB/EL/IMP/CAB 35,720 346,000 1.42 2.4381-20BP (59.8/31.4/1/7.8) X03513 SAIB/EL/IPM/CAB 3,274 4,092 1.02 1.74381-20 BP (71/23/1/5) X03514 SAIB/EL/IPM/CAB 2,892 14,349 1.61 2.83381-20BP (65/27/3.5/4.5) X03515 SAIB/EL/IPM/CAB 4,040-7,01031,221-30,427 1.7 2.74 381-20BP (65/27/3/5) X03516 SAIB/EL/IPM/CAB 2,92038,000 2.11 3.1 381-20BP (63/29/3/5) X03517 SAIB/EL/IPM/CAB 875 5,3001.97 2.84 381-20BP (63/29/3.5/4.5) X03518 SAIB/EL/IPM/CAB 4,040-7,01031,221-30,427 2 3.1 381-20BP (65/27/3/5) X03520 SAIB/EL/CAB 1,618-2,6705,270-9,380 1.64 2.5 171-15 (70/27/3)

TABLE 2 Exemplary CABs CAB types (supplied by Butyryl Acetyl HydroxylMelting Glass Molecular Eastman Content Content Content Point Tran. Wt(no. Chemicals (%) (%) (%) (° C.) Temp (° C.) avg) 171-15 17 29.5 1.5127-240 NA NA 381-2  36-38 13.5-14.5 1.3-1.7 171-185 130-133 40000381-20 36 15.5 0.8 185-196 128 66000-83000

CAB can have butyryl contents ranging from about 17% to about 38%,acetyl contents ranging from about 13% to about 30%, hydroxyl contentsranging from about 0.8% to about 1.7%, or a combination thereof.

Measurement of Drug Dissolution Rates in Low pH Solution (FIG. 7)

One soft gelcap containing one of several SAIB-oxycodone formulationswas placed in a standard glass beaker with a stirrer mechanism (asdefined by United States Pharmacopia Apparatus II; VK 7000 USP IIDissolution Tester). 900 ml of 0.1N HCL solution at 37° C. was placed inthe beaker and the solution was stirred at 50 rpm for 2 hours. Duringthis period, the gelcap dissolved and the SAIB drug formulation wasexposed to the low pH solution, and oxycodone dissolution begins. Anumber of 1 ml samples were taken and oxycodone concentration determinedby HPLC (Perkin Elmer Series 200 LC Pump, or equivalent; UV detector,Perkin Elmer Diode Array Detector 235C, or equivalent). Following theinitial dissolution step, the content of the beaker was modified toadjust pH from 1 to 6.8 by adding sodium phosphate buffer. Temperaturewas maintained at 37° C., and dissolution of drug continued foradditional 22 hours. Additional samples of 1 ml were taken at varioustime points and oxycodone concentration determined by HPLC. Thecumulative percentage of oxycodone dissolved into the media wascalculated for each time interval and a graph drawn (FIG. 7).

FIG. 7 show the data obtained from a drug dissolution experiment. Thegraph shows the data for a SAIB-drug formulation in a soft gelcap(square data points) compared with a commercial oxycodone tablet(OxyContin®) (diamond data points) that was used as a reference. They-axis represents cumulative percent of oxycodone released and thex-axis represents time (hrs).

The SAIB oxycodone formulation of FIG. 7 contained the following weightpercents of ingredients: oxycodone free base 10 mg per gelcap, SAIB 65%,ethyl lactate 27%, isopropyl myristate 3% and CAB 381-20 5%. Thecommercial oxycodone product contained 80 mg of oxycodone. A number ofother SAIB oxycodone gelcap formulations were tested for drugdissolution and results are given in Table 1.

It is apparent from FIG. 7 that the commercial oxycodone tablet showed alarge initial burst of oxycodone release with nearly 50% being deliveredwithin the first hour, and 80% delivered within six hours. The drugrelease following the burst was slow as compared with the initial burst.On the other hand, the SAIB oxycodone formulation showed no burst effectand displayed a more controlled and sustained release of the drug overthe entire testing period.

Extraction of Drug into Ethanol

An important feature of the invention is that formulations can be madesuch that extraction of drug from the formulations using traditionalethanol extraction (traditionally used by drug abusers) is much lessefficient than it is for the tablet and capsule formulations of theprior art.

FIGS. 1-4 and 11 are graphs that show results from an abuse-deterrencestudy. The aim was to determine the amount of oxycodone that could beextracted from a dosage form comprising a SAIB/oxycodone formulation ina soft gelcap using simple alcohol extraction, as used by drug abusers.The units of the graphs are percentage cumulative release vs. time(mins).

The method used to produce data for the abuse-deterrence study was asfollows. Each soft gelcap was filled with 0.75 ml of formulation and wasplaced in 18 ml of 0.1N HCL in a 60-mL amber bottle and shaken at 240RPM on an orbital shaker for 30 minutes. After 30 minutes, 12 ml of 2000(200 proof) ethanol was added to each bottle. The solutions were swirledby hand and a 1-ml sample was sampled from each bottle at T=0. Thesolutions were placed back in the orbital shaker for further shaking at240 RPM. 1 ml samples were taken after 10, 20, 30, 40, 60 and 180minutes of further shaking from each bottle. The results were graphed ona linear scale of cumulative release (%) vs. Time (mins).

FIG. 1 shows percentage cumulative amounts of drug extracted inpercentage of initial drug loading in SAIB formulations vs. time (mins)for 9 formulations. Each formulation contains 12 mg/ml oxycodone. Theformulation ID numbers and formulations component ratios are shown inthe key. The ratios (weight percent) of each ingredient correspond to:SAIB:EL:IM:CAB.

From the data presented in FIG. 1, it can be seen that all ingredientsand their ratios affect the extractability of drug. Using a regressionanalysis, the following empirical equation relating cumulative percentof drug extracted as a function of weight percent of each ingredient.Ln Cum %=4.04+0.0132x1+0.0518x2−0.1994x3:r ²=0.75  (equation 8)where Cum % indicates the cumulative percent of drug extracted over theentire time interval, and x1, x2 and x3 are the weight percents of EL,IPM and CAB 381-20. As can be seen, the weight percent of drug that wasextracted by the above described alcoholic solution decreased withincreasing CAB 381-20 (see formulations 256-62-02, 256-62-04, 256-62-06and 256-62-08). However, it was not obvious that the addition of wellknown rheology modifier, IPM, when added to the formulations containing4 wt. % of CAB 381-20, did not affect the alcohol extraction of the drugas demonstrated by Formulation 256-62-16. This is contrary to a commonsense in the art of pharmaceutical formulations. That is IPM, which is arheology modifier of SAIB, would have been predicted to loosened up theSAIB formulations and facilitated the drug extraction but it did not. Itwas also discovered that when the CAB content was 3 wt. % as informulation 256-62-12, addition of 3 wt. % of IPM increasedsignificantly the drug extractability by alcohol solution versus theformulations that did not contain IPM such as formulation 256-62-04. Itwas concluded therefore, that low drug extractability from SAIBformulations by alcohol can be brought about not only due to optimumweight percent of CAB but also due to an optimum ratio between CAB andIPM.

FIG. 2 shows cumulative percent of oxycodone free base extracted byalcohol vs. time (mins) for 4 formulations. Each formulation was filledinto soft gelcaps. Each gelcap contained 12 mg/ml oxycodone free base.

In this experiment the effects of different ratios of IPM to CAB wereevaluated for drug extractability from SAIB formulations by alcohol. Theratio varied from 0.25 to 0.78. For the given range of ratios, it wasdiscovered unexpectedly that increasing contents of ethyl lactate,isopropyl myristate and CAB in concert reduced the drug extractabilityby alcoholic solution. From this experiment, it was discovered that IPMand CAB were quantitatively reciprocally interchangeable, such thatincreasing one component and decreasing the other by the same wt %resulted in a formulation with unchanging rheological properties. Thisis particularly surprising discovery in light of the fact that IPM is arheology modifier that makes the SAIB formulation loose (less viscous)while CAB is supposed to make it more cohesive and less deformable. Onewould not have expected, therefore, that increasing IPM would have thesame effect as increasing CAB.

FIG. 3 shows cumulative percentage of drug extracted by alcoholicsolution from various SAIB formulations vs. time (mins) for 4formulations. Each formulation contains 12 mg/ml oxycodone. Theseformulations had IPM to CAB ratios ranging from 0.6 to 0.78 andcalibrated content of ethyl lactate ranging from 27-29 wt. %. The figuredemonstrates that at the end of 180 minute extraction experiment, thepercentage extracted was approximately the same for all 4 formulations.However, at the end of the first 60 minutes, it was discovered that thepercent extracted drug was higher with the formulations containinggreater amounts of ethyl lactate. It was also found that extremely ansmall increment in ethyl lactate content led to a large increase in theextraction of drug.

FIG. 4 Shows cumulative percentage of drug extracted by alcohol vs. time(mins) for 3 formulations. Each formulation contains 9 mg/ml oxycodone.This experiment demonstrated that ethyl lactate has greater influence onthe drug extractability by alcohol than CAB by a factor of more than 2fold. This was another unexpected discovery since it would have beenreasonable to believe that CAB is a extremely effective matrix/networkforming agent.

FIG. 11 shows the results of alcohol-extraction experiments. The graphdisplays a plots of % total oxycodone extracted into 40% ethanol+0.1NHCl vs. time. The control formulation used was a commercial 10 mgOxycontin® tablet. The experimental formulations used in this experimentdid not contain IPM and had the following ratios of SAIB:EL:CAB: “BaseFormula, high level”=50:45:5; “Base Formula, medium level”=60.8:37:2.2;“Base Formula, low level”=50:48:2. In this experiment, at about 30minutes, the gelatin capsule containing formulations disclosed hereinwas cut in half, and the tablet was crushed with a spatula. As can beseen, the OxyContin® tablet formulation rapidly releases 100% of drugafter crushing. After about 60 minutes, all the drug is released. Forthe three SAIB formulations, however, the % drug released after 60 minsis only about 13%, 23% and 30% for the low, medium and highformulations, respectively. These results clearly demonstrate that theformulations of the invention have significantly improvedabuse-deterrence characteristics when compared with the currentOxycontin® tablet formulation.

Extraction of Drug into Water

Another experiment was performed to determine the degree to which theformulation of the invention possessed abuse deterrent characteristics,specifically to determine the extractability of Oxycodone into water.Typically, a drug abuser may crush and grind an oxycodone tablet anddissolve it in water to extract the drug into aqueous solution forinjecting. In the present experiment, the experimental dosage form was aSAIB-oxycodone gelcap with a formulation of SAIB:EL:IPM:CAB at a ratioof 67:26:3:4, contained in a soft gelatin capsule, and containing 9 mgof drug (oxycodone free base). The control dosage form used was a 9 mgOxycontin® tablet. Each dosage form was crushed with a mortar and pestleand ground in 5 ml water. The resulting solution/suspension was thenfiltered through a 0.45 micron filter into a flask and diluted to 50 mlwith water. Oxycodone concentration was then quantified by HPLC. Theresults were as follows: For the control (OxyContin® tablets), 100% ofthe oxycodone was extracted from the crushed tablet into water. For theexperimental SAIB formulation, only about 21% of oxycodone extractedinto water. This shows that the current formulation has considerabledrug-abuse deterrence characteristics when compared with the Oxycontin®tablet, because the drug cannot be efficiently extracted into water.

Physical Treatment

Another potential method for drug abuse is to lower the temperature andmechanically crush a drug formulation so as to produce a powder whichthen can be inhaled or dissolved in a solution for injection. Anexperiment was performed to determine the characteristics of the currentformulation, specifically with regard to lowering the temperature andcrushing. In this procedure the formulation was placed in a laboratoryfreezer at −80° C. for eight hours, after which it was struck sharplywith a hammer. One formulation comprised 100% SAIB, one formulationcomprised SAIB plus a solvent (26% EL), and one formulation was aformulation of SAIB:EL:IPM:CAB at a ratio of 67:26:3:4 and oxycodonefree base (see above). For the first formulation (100% SAIB) the resultswere as follows: Within about 45 seconds of being crushed, the fragmentsthawed and returned to the state of a high viscosity liquid. Thecontrolled release matrix structure of the formulation was preserved.For the second formulation (SAIB+solvent): Within about 30 seconds afterbeing crushed the formulation mass appeared highly viscous and stickyand did not fracture into discreet fragments. Again, the controlledrelease matrix structure was preserved. For the PTI-821 formulation:Within about 30 seconds after being crushed the formulation appearedhighly viscous and tacky and did not fracture into fragments. Onceagain, the controlled release matrix structure was preserved.Consequently, attempted abuse by lowering temperature and crushing wouldnot result in a readily abusable form of drug. See FIGS. 8-10.

Plasma Level Study

FIG. 5 is a graph from a dog PK study showing plasma concentration(ng/ml) vs. time (hr) for three SAIB soft gelcaps containing 9 mgoxycodone formulations (A, B and C) and Oxycontin® (A=SAIB:EL:CAB;B=SAIB:EL:CAB; C=SAIB:EL:CAB, CAB=CAB 171-15). A single gelcapcontaining about 0.75 g of each of oxycodone formulations wasadministered to a dog orally. Blood was drawn periodically over 12 hoursand the plasma concentration of oxycodone was determined as a functionof time.

Plasma vs. time profiles for three formulations A, B and C, werecompared against that for Oxycontin®. The SAIB gelcap formulations andthe Oxycontin® tablets each contained an identical amount of oxycodonefree base (9 mg).

SAIB formulations A and C exhibited higher Cmax (maximum plasmaconcentration of drug) values than the Oxycontin® tablet formulation.The two SAIB formulations A and B had a significantly shorter Tmax (timeto maximum plasma level) values compared with Oxycontin®. On the otherhand, SAIB formulation B which has a highest viscosity of A, B and C,shows equivalent Cmax but longer Tmax values compared with theOxycontin® control.

SAIB formulations A and C also gave greater AUC (area under the plasmadrug concentration vs. time curve) values and bioavailability due totheir unique rheological (flow) characteristics compared to Oxycontin®reference. It was discovered that optimum SAIB formulations, whichmanifest desirable pharmacokinetic profiles, must possess the followingviscosity characteristics: the SAIB solution viscosity at 37° C. shouldbe in the range from 1,000-30,000 cP. Further more the SAIB formulationsfollowing immersion in 37° C. water or aqueous buffer (pH 1-10) for 4-5hours should optimally have the viscosity at 37° C. ranging from3,000-50,000 cP.

Although a number of the examples provided above relate to compositionsaccording to the invention containing oxycodone in amounts ofapproximately 10 mg per SAIB formulation gelcap, larger or smalleramounts of drug (e.g., 5 mg, 20 mg, 40 mg, 80 mg, 160 mg, and the like)can be incorporated into SAIB gelcaps according to the invention.

While the benefits of the invention have been described with respect tocertain drugs, such as opioids, some or all of these benefits areobtained when the formulation of the invention is used with a widevariety of drugs, such as immunosuppressants, antioxidants, anesthetics,chemotherapeutic agents, steroids (including retinoids), hormones,antibiotics, antivirals, antifungals, antiproliferatives,antihistamines, anticoagulants, antiphotoaging agents, melanotropicpeptides, nonsteroidal and steroidal anti-inflammatory compounds,antipsychotics, and radiation absorbers, including UV-absorbers,chemotherapeutic agents, anti-nausea medication, and the like.Non-limiting examples of pharmacological materials or drugs suitable foruse in the invention include anti-infectives such as nitrofurazone,sodium propionate, antibiotics, including penicillin, tetracycline,oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin,neomycin, polymyxin, gramicidin, chloramphenicol, erythromycin, andazithromycin; sulfonamides, including sulfacetamide, sulfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, andanti-virals including idoxuridine; antiallergenics such as antazoline,methapyritene, chlorpheniramine, pyrilamine prophenpyridamine,hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone,dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone,prednisolone, prednisolone 21-sodium succinate, and prednisoloneacetate; desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen; vaccines such assmallpox, yellow fever, distemper, hog cholera, chicken pox, antivenom,scarlet fever, dyptheria toxoid, tetanus toxoid, pigeon pox, whoopingcough, influenzae rabies, mumps, measles, poliomyelitic, and Newcastledisease; decongestants such as phenylephrine, naphazoline, andtetrahydrazoline; miotics and anticholinesterases such as pilocarpine,esperine salicylate, carbachol, diisopropyl fluorophosphate, phospholineiodide, and demecarium bromide; parasympatholytics such as atropinesulfate, cyclopentolate, homatropine, scopolamine, tropicamide,eucatropine, and hydroxyamphetamine; sympathomimetics such asepinephrine; sedatives and hypnotics such as pentobarbital sodium,phenobarbital, secobarbital sodium, codeine, (a-bromoisovaleryl) urea,carbromal; psychic energizers such as 3-(2-aminopropyl) indole acetateand 3-(2-aminobutyl) indole acetate; tranquilizers such as reserpine,chlorpromayline, and thiopropazate; androgenic steroids such asmethyl-testosterone and fluorymesterone; estrogens such as estrone,17-.beta.-estradiol, ethinyl estradiol, and diethyl stilbestrol;progestational agents such as progesterone, megestrol, melengestrol,chlormadinone, ethisterone, norethynodrel, 19-norprogesterone,norethindrone, medroxyprogesterone and 17-.beta.-hydroxy-progesterone;humoral agents such as the prostaglandins, for example PGE₁, PGE₂ andPGF₂; antipyretics such as aspirin, sodium salicylate, and salicylamide;antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide; antimalarials such as the 4-aminoquinolines,8-aminoquinolines, chloroquine, and pyrimethamine, antihistamines suchas diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, andchlorphenazine; cardioactive agents such as dibenzhydroflume thiazide,flumethiazide, chlorothiazide, and aminotrate; nutritional agents suchas vitamins, natural and synthetic bioactive peptides and proteins,including growth factors, cell adhesion factors, cytokines, andbiological response modifiers.

The embodiments disclosed herein are exemplary only, and are not meantto limit the invention, which should be interpreted solely in light ofthe claims.

1. An oral formulation comprising: oxycodone; sucrose acetateisobutyrate (SAIB); a cellulose acetate butyrate (CAB) having a numberaverage molecular weight ranging from 66,000 Daltons to 83,000 Daltons;isopropyl myristate (IPM); and a solvent selected from the groupconsisting of triacetin and ethyl lactate (EL).
 2. The oral formulationof claim 1, wherein the solvent is triacetin.
 3. The oral formulation ofclaim 1, wherein the CAB has a butyryl content ranging from about 17% toabout 38%.
 4. The oral formulation of claim 1, wherein the CAB has anacetyl content ranging from about 13% to about 30%.
 5. The oralformulation of claim 1, wherein the CAB has a hydroxyl content rangingfrom about 0.8% to about 1.7%.
 6. The oral formulation of claim 1,wherein the CAB has a butyryl content ranging from about 17% to about38%, an acetyl content ranging from about 13% to about 30%, and ahydroxyl content ranging from about 0.8% to about 1.7%.
 7. The oralformulation of claim 1, wherein the formulation comprises from about 1to about 8.6 weight percent of the CAB.
 8. The oral formulation of claim1, wherein the formulation comprises from about 20 to about 50 weightpercent of the solvent.
 9. The oral formulation of claim 1, wherein theformulation comprises from about 1 to about 75 weight percent IPM. 10.An oral dosage form comprising the formulation of claim 1, wherein theformulation is contained in a capsule.
 11. The oral dosage form of claim10, wherein the capsule comprises gelatin or hydroxyl propylmethylcellulose.
 12. The oral dosage form of claim 10, wherein the capsule isa hard capsule comprising gelatin or hydroxyl propylmethyl cellulose.13. The oral formulation of claim 1, wherein the formulation comprises:from about 1 to about 8.6 weight percent of the CAB; from about 20 toabout 50 weight percent of the solvent; and from about 1 to about 75weight percent IPM.
 14. The oral formulation of claim 13, wherein theformulation comprises from 3 to 7.8 weight percent of the CAB.
 15. Theoral formulation of claim 14, wherein the CAB has a butyryl contentranging from about 17% to about 38%.
 16. The oral formulation of claim14, wherein the CAB has an acetyl content ranging from about 13% toabout 30%.
 17. The oral formulation of claim 14, wherein the CAB has ahydroxyl content ranging from about 0.8% to about 1.7%.
 18. The oralformulation of claim 14, wherein the CAB has a butyryl content rangingfrom about 17% to about 38%, an acetyl content ranging from about 13% toabout 30%, and a hydroxyl content ranging from about 0.8% to about 1.7%.19. An oral dosage form comprising the formulation of claim 14, whereinthe formulation is contained in a capsule.
 20. The oral dosage form ofclaim 19, wherein the capsule comprises gelatin or hydroxyl propylmethylcellulose.
 21. The oral dosage form of claim 19, wherein the capsule isa hard capsule comprising gelatin or hydroxyl propylmethyl cellulose.22. A method of providing pain relief to a subject in need thereof, themethod comprising: orally administering to the subject an effectiveamount of the oral dosage form of claim
 13. 23. A method of providingpain relief to a subject in need thereof, the method comprising: orallyadministering to the subject an effective amount of the oral formulationof claim 1.